There are a number of chemical processes for transformation of 17-keto steroids to the corresponding 17.alpha.-hydroxypregna steroids, see U.S. Pat. No. 4,041,055 and Tetrahedron Letters 22, 2005 (1971). Likewise, chemical processes are known for the transformation of 17-keto steroids to the corresponding corticoids, see U.S. Pat. Nos. 4,041,055, 4,342,702, 4,216,159, and Great Britain Pat. No. 2,086,907A.
The literature also sets forth processes for the transformation of the 17.beta.-cyano-17.alpha.-hydroxy steroid (I) to the corresponding 17.alpha.-acyloxyprogesterone (VI) ses P. deRuggieri, et al., J. Am. Chem. Soc. 81, 5725 (1959); J. C. Gasc, et al., Tetrahedron Letters 22, 2005 (1971); A. Belanger, Steroids 37, 361 (1981); and Japanese Pat. Nos. J5 7,062,296, J5 7,062,297, J5 7,062,299 and J5 7,062,300.
17.beta.-Cyano-17.alpha.-hydroxy steroids (I) have been produced from the corresponding 17-keto steroids, see A. Ercoli, et al., J. Am. Chem. Soc. 75, 650 (1953); H. Heusser, et al., Helv. Chem. Acta 33, 1093 (1950); K. Meyer, Helv. Chim. Acta 29, 1580 (1946); K. Miescher, et al., Helv. Chim. Acta 21, 1317 (1938); H. Kuhl, et al., Steroids 28, 89 (1976), U.S. Pat. No. 3,496,169 and East German Pat. No. 147,669. Japanese Pat. Nos. J5 7,062,296, J5 7,062,299 and J5 7,062,300 also include 17.beta.-cyano-17.alpha.-hydroxyandrost-4,9(11)-dienes (IA). J. C. Gasc, et al., Tetrahedron Letters 22, 2005 (1971) reported the preparation of 19-nor-17.beta.-cyano-17.alpha.-hydroxyandrost-5(10),9(11)-dienes.
17.beta.-Cyano-17.alpha.-hydroxy steroids (I) are known where the 17.alpha.-hydroxy group is protected as an ester. See, for example, Helv. Chem. Acta 29, 1580 (1946) formula IV on p. 1582 and Helv. Chem. Acta 33, 1093 (1950) formula XIII on p. 1096. These compounds are also known where the 17.alpha.-hydroxy group is protected as an ether (II). See, for example, Steroids 37, 362 (1981) on p. 362 the TMS ether; J. Am. Chem. Soc. 81, 5725 (1959) on p. 5726 formula III as the THP ether; Tetra. Lett. 22, 2005 (1971) on p. 2007 formula IX as the TMS ether; and Japanese Pat. No. 7,062,296 for the butyl vinyl ether. U.S. Pat. No. 4,348,327 discloses 17.beta.-cyano-17.alpha.-hydroxy steroids of the .DELTA..sup.4 -3-keto (A) and 3.beta.-hydroxy-.DELTA..sup.5 (C) type which may or may not have methyl substitution at C.sub.16 but which have no substitution in the C ring.
D. H. R. Barton, et al., J.C.S. Chem. Comm. 774 (1981) reported producing a 3.beta.-O-substituted-.DELTA..sup.5 -enimide similar to the enimide (III) where the protecting group at 17.alpha. was acetate and the substituent on the enimide nitrogen at C.sub.20 was --CHO. It should be noted that Barton, et al. did not produce his 3.beta.-O-substituted-.DELTA..sup.5 -enimide from a 17.beta.-cyano-17.alpha.-hydroxy steroid (II) but rather produced it by a different process from a 17(20)-unsaturated steroid.
R. B. Boar, et al., in J. C. S. Perkin I 1242 (1975) reported a 3.beta.-acetoxy-.DELTA..sup.5 -20-acetyl enimide, starting with a pregnenolone derivative. While these compounds are somewhat similar to the enimide (III) of the present invention, the prior art compounds disclose an ester at the 17.alpha. position. The present process has the flexibility to produce the enimide (III) where the C.sub.17 hydroxyl group is protected with an ether not an ester (acetate). The ester protecting group of the prior art processes has the disadvantage of being difficult to remove, whereas, the C.sub.17 ethers of the present invention do not have that problem. Again, the enimide produced by Boar, et al. was produced from a different starting material by a process different than that of the present invention, i.e. the transformation of the 17-protected 17.beta.-cyano-17.alpha.-hydroxy steroid (II) to the enimide (III).
The .DELTA..sup.20 -enamide acylate (IV) is known where the steroid A-ring is 3.beta.-hydroxy-.DELTA..sup.5 (C). Boar et al. produced their .DELTA..sup.20 -enamide acylate from the corresponding 3.beta.-acetyl-.DELTA..sup.5 -enimide by reaction with acetic acid containing trichloroacetic acid. See R. B. Boar, et al., J.C.S. Perkin I 1242 (1975). That compound had no substitution in the C-ring. The .DELTA..sup.4 -3-keto-(A) and .DELTA..sup.1,4 -3-keto-(B)-.DELTA..sup.20 -enamide acylates of the present inventions are easier to convert to the commercial corticoid products than is the compound dislosed by Boar, et al.
The .DELTA..sup.20 -enamide (V) is a tautomer of the enimide (III). Boar, supra, disclosed a .DELTA..sup.20 -enamide. That compound, compound IV on p. 1243, differs from the .DELTA..sup.20 -enamide (V) in that at C.sub.17 the group is an ester, whereas, the .DELTA..sup.20 -enamides (V) must have an ether or hydroxy group at C.sub.17. It has been found that use of ethers at C.sub.17 (--OZ) permit the reaction of the 17-protected-17.beta.-cyano-17.alpha.-hydroxy steroid (II) with Grignard reagents to produce the enimide (III) and further the .DELTA..sup.20 -enamide (V). D. H. R. Barton, et al., J.C.S. Chem. Comm. 774 (1981) also discloses a .DELTA..sup.20 -enamide 17-acetate, see compound (5). That compound further differs from the .DELTA..sup.20 -enamides (V) of the present invention in that the substituent on the enamide nitrogen atom is an aldehyde (a formyl group) in Barton but is an acyl group in the present invention.
Boar, supra, discloses the transformation of an enimide-17-ester to a .DELTA..sup.16 -progesterone. The process of the present invention involves the transformation of an enimide-17.alpha.-ether (III, Z is not a hydrogen atom) or its tautomer, a .DELTA..sup.20 -enamide-17-ether (V) to a .DELTA..sup.20 -enamide 17-ester (IV), by an ether to ester exchange followed by hydrolysis to give a progesterone 17-acylate (VI). Boar discloses the hydrolysis of an enimide 17-acetate to a 20-keto-17-acetate (VI). The process of the present invention dos not include the enamide 17-acetate of Boar or the process of its formation.
The oxazoline (IX), structure type, is known, see Great Britain Pat. No. 2,086,907A and J.C.S. Chem. Comm. 774 (1981). D. H. R. Barton, et al. in J.C.S. Chem. Comm. 774 (1981) transformed a .DELTA..sup.17(20) -20-amide to the oxazoline by reactions with a peracid whereas the process of the present invention starts with an enimide (III). Barton, et al. proposed a mechanism for his reaction involving an 17,20-epoxide and a 17.alpha.-hydroxy-20-enimide. However, none of the intermediates were isolated, identified or the mechanism proved. The 21-bromo-20-formaldimine 17-acetate (XVI) is disclosed by Barton, supra.
The 21-halo-.DELTA..sup.20 -enamides (XX) are not known. The unhalogenated .DELTA..sup.20 -enamide 17-acylate is known where the steroid A-ring is of the 3.beta.-hydroxy-.DELTA..sup.5 series, see Boar and Barton supra. With ether substitution at C-17, the unhalogenated .DELTA..sup.20 -enamide 17-ethers are unknown regardless of the substitution in the A-ring.
By the process of the present invention the .DELTA..sup.20 -enamide (V) is converted into the corresponding 21-halo enimide (XV) in a one-step process. D. M. R. Barton, et al., JCS Chem. Comm., 774 (1981) disclosed the transformation of a .DELTA..sup.20 -enamide (5), where the nitrogen was substituted with a formamide to the 21-bromo enimide (6) where both contain the 17-acetate.
The 21-halo enimide (XV) can be transformed to the 17.alpha.-hydroxy-21-bromo steroid (XIII) directly or indirectly via the 21-halo-.DELTA..sup.20 -enamide (XX). Barton, supra, disclosed transformation of the 21-bromo steroid (7) to the 21-bromo-20-keto steroid (8) in which the ester at C-17 was not lost. The process of the present invention produces the free 17.alpha.-hydroxy-21-bromo-20-keto steroid (XIII).
BRIEF DESCRIPTION OF THE INVENTION
Disclosed are 17.beta.-cyano-17.alpha.-hydroxy (IB), 17-protected-17.beta.-cyano (IIB), enimide (III A-C), .DELTA..sup.20 -enamide (V A-C), 21-haloenimide (XV A-C), 21-halo-.DELTA..sup.20 -enamide (XX A-C), .DELTA..sup.20 -enamide acylate (IV A,B), 17.beta.-cyano-17.alpha.-hydroxy (IC) and 17.beta.-cyano-17.alpha.-hydroxy (IA') steroids.
Disclosed is a process for the preparation of a C.sub.3 protected form of an enimide (III A-C) which comprises (1) contacting a C.sub.3 protected form of a 17-protected-17.beta.-cyano-17.alpha.-hydroxy steroid (II A-C) with a methylating agent and contacting the product of step (1) with an acylating or silating agent.
Also disclosed is a process for the preparation of a C.sub.3 protected form of a .DELTA..sup.20 -enamide acylate (IV A-C) which comprises contacting a steroid selected from the group consisting of a C.sub.3 protected form of an enimide (III A-C) or a C.sub.3 protected form of a .DELTA..sup.20 -enamide (V A-C) with a carboxylic acid of the formula R.sub.17 COOH and an anhydride of the formula (R.sub.17 CO).sub.2 O where R.sub.17 is a hydrogen atom alkyl of 1 thru 5 carbon atoms, phenyl substituted with zero thru 2 chlorine atoms, trichloromethyl or trifluoromethyl groups.
Further disclosed is a process for the preparation of a C.sub.3 protected form of a .DELTA..sup.20 -enamide (V A-C) which comprises contacting a C.sub.3 -protected form of an enimide (III A-C) with an acid or base.
Also disclosed is a process for the preparation of a C.sub.3 protected form of an oxazoline (IX A-C) which comprises contacting a steroid selected from the group consisting of a C.sub.3 protected form of an enimide (III A-C) or a C.sub.3 protected form of a .DELTA..sup.20 -enamide (V A-C) with an acid in an organic solvent or mixtures thereof.
Further disclosed is a process for the preparation of a steroid selected from the group consisting of a C.sub.3 protected form of a 21-halo enimide (XV A-C) and a C.sub.3 protected form of a 21-halo-.DELTA..sup.20 -enamide (XX A-C) which comprises contacting a C.sub.3 protected form of a .DELTA..sup.20 -enamide (V A-C) with a halogenating agent.
Further disclosed is a process for preparing a C.sub.3 protected form of a 17.alpha.-hydroxy steroid (XIII A-C) which comprises (1) contacting a steroid selected from the group consisting of a C.sub.3 protected form of a 21-halo enimide (XV A-C) or a C.sub.3 protected 21-halo-.DELTA..sup.20 -enamide (XXA-C) with an aqueous acid.